Exposure to high levels of circulating estrogens unopposed by progestins is the primary cause of endometrial cancer. However, little is known about whether environmental contaminants that mimic the effects of estrogen increase the risk of this disease. Cadmium is a trace metal released into air and soil as a byproduct of industrial processes and is perhaps the most potent of these estrogenic contaminants with respect to endometrial cancer etiology. Major sources of non-occupational exposure to Cd include cigarette smoke, diet, and inhalation of ambient air contaminated by industrial processes and combustion of fossil fuels. This proposed study will test the emerging hypothesis that greater levels of Cd exposure increase endometrial cancer risk by utilizing existing data on dietary intake, residence, smoking history, and other risk factors and urine specimens from 356 women diagnosed with endometrial cancer and 683 matched controls enrolled in the Nutrition, Estrogens and Endometrial Cancer in Teachers (NEET) study, a nested case-control study within the California Teachers Study (CTS) cohort. The availability of these data, urine specimens for the measurement of Cd concentration-a classic measure of chronic exposure, and existing databases of environmental and dietary sources of Cd, will allow us to conduct a comprehensive assessment of exposure that incorporates a myriad of sources and evaluates the relative contribution of each source. This will also allow us to assess whether any observed elevations in risk are heterogeneous across exposure sources. The specific aims of this study will be to: 1) characterize exposure to Cd from dietary and environmental sources for all cases and controls in the NEET study; 2) evaluate the contributions of dietary intake and exposure from environmental sources on Cd concentrations measured in urine; and 3) estimate the effects of dietary, environmental, and total Cd exposure on the risk of endometrial cancer. The emerging evidence that Cd is a potential risk factor for endometrial cancer suggests a future direction for minimizing dietary and environmental exposures to this toxic metal. This study offers a unique and timely opportunity to improve our understanding of whether Cd plays an etiologic role in the development of this cancer and identify important, and potentially modifiable, sources of exposure to this metal. PUBLIC HEALTH RELEVANCE: Cadmium is a toxic metal known that is classified as a human carcinogen and is suspected of having estrogenic properties. By evaluating whether the risk of endometrial cancer is increased by exposure to cadmium, this proposed study offers a unique and timely opportunity to improve our understanding of a potentially modifiable risk factor for this disease and identify specific sources of cadmium that could be targeted for minimizing exposure.